Biomedical subjects

J Bénavidès

Publications and source records attributed to J Bénavidès.

11 recordsLinked to original sources

PubMed1997

Effects of amisulpride, an atypical antipsychotic which blocks preferentially presynaptic dopamine autoreceptors, on integrated functional cerebral activity in the rat.

Amisulpride, a benzamide derivative with an atypical neuroleptic profile relieves the negative symptoms of schizophrenia when administered at low doses (50-150 mg). In an attempt to define the anatomical substrates involved in this action we have studied the effects of amisulpride on regional cerebral glucose utilisation (RCGU) in the awake lightly restrained rat, by quantitative autoradiography using [14C]2-deoxyglucose ([14C]2-DG). Amisulpride was administered 1 h before [14C]2DG i.v. injection, at a dose of 5 mg/kg which resulted in a striatal D2 receptor occupancy of 10% similar to that induced by doses of this compound used for the treatment of negative symptoms of schizophrenia. Amisulpride induced significant RCGU increases in cortical areas, in visual relays, in auditory structures and in several limbic structures. The pattern of changes in RCGU seen with amisulpride clearly differs from that of haloperidol, given at a dose resulting in a similar occupancy of striatal D2 receptors (0.01 mg/kg), which was mostly ineffective. The amisulpride-induced activation of RCGU in specific brain areas involved in the control of cognitive functions and motivational and emotional behavior, may at least in part, explain the efficacy of this compound in the treatment of negative symptoms of schizophrenia.

Amisulpride↗

PubMed1991

Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission.

Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response. Similarly, NAN-190 (0.1 microM) almost totally prevented the inhibition by 8-OH-DPAT (1 microM) of forskolin-stimulated adenylate cyclase activity in adult rat hippocampal slices but, per se, was without effect on the forskolin response. These results indicate that NAN-190 is a potent antagonist at postsynaptic 5-HT1A receptors in vitro. However, NAN-190 also potently antagonized (IC50 = 0.16 nM) the stimulation by norepinephrine of phosphoinositide turnover in rat cortical slices. In this respect NAN-190 was a 250-fold more potent antagonist than prazosin (IC50 = 49 nM). Thus, in addition to its 5-HT1A receptor antagonist properties, NAN-190 has potent alpha 1-adrenoceptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Differential modulation of [3H]TCP binding to the NMDA receptor by L-glutamate and glycine.

At equilibrium (4 h incubation), [3H]TCP (N-(1-[2-thienyl]-cyclohexyl)-3,4-[3H]piperidine) binding to well-washed rat forebrain membranes was enhanced in a concentration-dependent and 2-APV (2-amino-5-phosphonovaleric acid)-sensitive fashion by L-glutamate (EC50 = 0.2 microM; maximal effect +280%). L-glutamate (10 microM) increased the affinity of [3H]TCP from 78 to 28 nM, but was without effect on the maximal binding capacity. The enhancing effect of L-glutamate on [3H]TCP binding was potentiated by glycine in a concentration-dependent manner (EC50 = 50 nM, maximal effect +30% in the presence of 10 microM L-glutamate; EC50 = 2 microM, maximal effect +29% in the presence of 0.1 microM L-glutamate). This effect was strychnine-insensitive. Glycine failed to enhance [3H]TCP binding in the presence of 10 microM 2-APV. The glycine effect was due to an increase in affinity (Kd = 21 nM in the presence of 10 microM glycine and 10 microM L-glutamate); glycine did not affect the maximal binding capacity. The glycine enhancement of L-glutamate-stimulated [3H]TCP binding was not antagonised by 1 microM strychnine and was mimicked by L-serine and L-alanine but not by GABA, taurine or beta-alanine. Kinetic analysis of the glycine and L-glutamate enhancement of [3H]TCP binding indicated that the L-glutamate effect was related to a decrease in the [3H]TCP dissociation rate while the glycine effect was due to an increase in the rate of [3H]TCP association in the presence of L-glutamate.

Animals↗

PubMed1988

5-HT1A receptor agonists inhibit carbachol-induced stimulation of phosphoinositide turnover in the rat hippocampus.

The selective 5-HT1A agonists, 8-hydroxy-2-(di-n-dipropylamino)tetralin (8-OH-DPAT) and ipsapirone, and the 5-HT1A/5-HT1B agonist, 1-(m-trifluoromethylphenyl)piperazine, partially inhibited the carbachol-stimulated [3H]inositol phosphate formation in rat hippocampal slices. The effect of 8-OH-DPAT was antagonized by cyanopindolol. Selective 5-HT1B, 5-HT2 and 5-HT3 agonists were inactive. 8-OH-DPAT failed to affect the phosphoinositide turnover stimulated by KCl, quisqualate or noradrenaline in hippocampal slices and by carbachol in striatal or cortical slices. These results suggest that 5-HT1A receptors are negatively coupled to phosphoinositide phosphodiesterase in the hippocampus.

Animals↗

PubMed1988

Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat.

Seven days after unilateral middle cerebral artery occlusion in rats, peripheral type benzodiazepine binding sites (PTBBS), using [3H]PK 11195 as a specific radioligand, were greatly increased in the cortical and striatal regions surrounding the focus of infarction with smaller increases in the ventrolateral and posterior thalamic complexes and in the substantia nigra, all ipsilateral to the occlusion. Similarly, PTBBS increases were observed in the caudate nucleus and entorhinal cortex of cats likewise subjected to prior unilateral occlusion of the middle cerebral artery. Intrastriatal administration of N-methyl-D-aspartate (250 nmol) in the rat resulted in a dramatic ipsilateral increase in PTBBS levels in the striatum and in the deeper laminae of the ipsilateral frontoparietal cortex. Intrastriatal kainic acid administration (12 nmol) also elicited PTBBS increases ipsilaterally in rat striatum and cortex; a bilateral elevation of PTBBS levels was observed in the hippocampus. With all these interventions there existed a good spatial correlation between the PTBBS increase and neuronal loss as assessed either histologically or by the autoradiographic detection of the putative neuronal marker [3H]SCH 23390 (a D1 dopamine receptor ligand). Moreover, a glial proliferation of non-neuronal cells (macrophage and glial cells) was observed in brain regions noted to have increased PTBBS levels. PTBBS autoradiography thus constitutes a suitable technique for the localization of damaged areas in several experimental models of brain injury. PTBBS label not only the primary lesions but also functionally related areas and could further our understanding of phenomena such as partial neuronal loss and diaschisis. The study of PTBBS could be envisaged for the detection, localization and quantification of all neuropathological situations which engender a glial reaction or macrophage invasion and is potentially applicable to both experimental and human subjects, in which both autoradiographic and tomographic approaches could be undertaken.

Animals↗

PubMed1986

Stereoselective inhibition of the binding of [3H]PK 11195 to peripheral-type benzodiazepine binding sites by a quinolinepropanamide derivative.

The specific binding of [3H]PK 11195 to the peripheral-type benzodiazepine binding site is inhibited by the l-enantiomer of N,N-diethyl-alpha-methyl-2-phenyl-4-quinolinepropanamide ((-)Q1) but not by its d-enantiomer ((+)Q1). (-)Q1 inhibited [3H]PK 11195 binding to several rat tissues with an IC50 of less than 10 nM whereas (+)Q1 was at least 500 times less potent. This stereoselectivity was observed in all the tissues tested (brain, heart, kidney and adrenals). The same stereoselectivity was found for the displacement of the binding of [3H]PK 11195 in vivo, where (-)Q1 had an ID50 between 4-15 mg/kg and (+)Q1 was completely inactive at all doses tested (i.e. up to 40 mg/kg). Neither isomer had appreciable affinity for central-type benzodiazepine binding sites ([3H]diazepam) nor for voltage-sensitive calcium channels ([3H]PN 200210 and [3H]verapamil).

Adrenal Glands↗

PubMed1985

Quantitative autoradiography of [3H]indalpine binding sites in the rat brain: I. Pharmacological characterization.

The binding of [3H]indalpine (4-[2-(3-indolyl)]ethyl piperidine) to slide-mounted sections of rat brain has been characterized. This 5-hydroxytryptamine (5-HT) uptake blocker binds to sections with high affinity (KD approximately 1 nM). The binding is saturable, and can be displaced by the addition of clomipramine (1 microM). Other drugs inhibiting the uptake of 5-HT also have the capacity to inhibit the binding of [3H]indalpine. A significant correlation (r = 0.86) was found between the capacity of these compounds to inhibit the uptake of 5-HT and their potencies as inhibitors of [3H]indalpine binding. Binding was Na+ - and Cl- -dependent and was inhibited competitively by 5-HT. Furthermore, electrolytic lesions of the dorsal raphe or medial forebrain bundle, which cause a degeneration of 5-HT cell bodies and fibers, respectively, resulted in a 30-40% reduction in the binding of [3H]indalpine. [3H]Indalpine binds to the 5-HT uptake recognition sites in a different manner from imipramine-like compounds.

Animals↗

PubMed1985

Quantitative autoradiography of [3H]indalpine binding sites in the rat brain: II. Regional distribution.

The localization of binding sites for [3H]indalpine to sections of rat brain was studied by a quantitative autoradiographic technique. Binding sites for this specific neuronal 5-hydroxytryptamine (5-HT) uptake inhibitor are concentrated in areas rich in 5-HT neuronal cell bodies, fibers, and synaptic terminals. One of the most interesting features of this regional distribution is the very high density of these sites found in the dorsal raphe, substantia nigra, ventral tegmental area, and locus ceruleus. Components of the visual system also show pronounced labelling with [3H]indalpine. The finding that limbic structures are strongly labelled by this drug may be related to the antidepressant activity of indalpine. The anatomical distribution of binding sites demonstrated is consistent with the specific labelling of 5-HT neurons by [3H]indalpine and confirms previous studies carried out with another 5-HT uptake inhibitor, [3H]imipramine.

Animals↗

PubMed1984

Histidine modification with diethylpyrocarbonate induces a decrease in the binding of an antagonist, PK 11195, but not of an agonist, RO5-4864, of the peripheral benzodiazepine receptors.

[3H]PK 11195 binding to peripheral type benzodiazepine binding sites in kidney membranes is inhibited by the histidine blocking agent diethylpyrocarbonate. This reagent irreversibly decreases the Bmax for [3H]PK 11195 without affecting the affinity. By contrast binding of [3H]RO5-4864 is not affected by diethylpyrocarbonate treatment. However RO5-4864 can protect in a concentration dependent manner the [3H]PK 11195 binding site from diethylpyrocarbonate whereas clonazepam and RO15-1788 are not active. These results suggest that PK 11195 and RO5-4864 interact with different conformational states of the receptors that RO5-4864. This is in agreement with our previous hypothesis that PK 11195 is an antagonist and RO5-4864 an agonist at the "peripheral type" benzodiazepine receptors.

Animals↗

PubMed1984

Opposite effects of an agonist, RO5-4864, and an antagonist, PK 11195, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J mice.

Two compounds with high affinity for the "peripheral type" benzodiazepine binding sites, PK 11195 (an isoquinoline derivative) and RO5-4864 (a benzodiazepine derivative) can modify the sensitivity of DBA/2J mice to audiogenic seizures. RO5-4864 (1-15 mg/kg) facilitates in a dose-dependent manner the audiogenic seizures and PK 11195 (2-5 mg/kg) antagonizes the RO5-4864 effects. At these doses PK 11195 alone does not modify the sensitivity to audiogenic seizures, but at doses between 20-80 mg/kg it protects DBA/2J mice against audiogenic seizures. By contrast PK 11195 is inactive against the facilitation of audiogenic seizures by ethyl-beta-carboline-3-carboxylate (a brain benzodiazepine receptor inverse agonist) and against the seizure elicited in absence of noise stimuli by RO5-4864 at doses between 20-40 mg/kg. These results suggest that facilitation by RO5-4864 of the audiogenic seizures and its antagonism by PK 11195 are mediated by the peripheral type benzodiazepine binding sites and agree with the thermodynamic analysis of the binding data which suggested that RO5-4864 might be an agonist and PK 11195 an antagonist. The good correlation between pharmacological effects and the occupancy degree of the binding sites as measured by the displacement of the "in vivo" [3H]-PK 11195 binding give an additional support to binding sites mediated effects.

Acoustic Stimulation↗

PubMed1984

Autoradiographic localization of peripheral benzodiazepine binding sites in the cat brain with [3H]PK 11195.

"Peripheral type" benzodiazepine binding sites were labelled in cat brain membranes by using [3H]PK 11195. This ligand binds to the "peripheral type" binding sites in a reversible, specific and saturable manner. Cat brain binding sites density (congruent to 6 pmol/mg prot.) was higher than in the rat. Pharmacological specificity was demonstrated by the potency order of displacing agents: PK 11195 greater than RO5-4864 greater than dipyridamole greater than diazepam greater than clonazepam. A similar characterization was performed in slide mounted brain sections where [3H]PK 11195 also labelled the "peripheral type" benzodiazepine binding sites. The high percentage of specific binding (80%) at 1 nM of [3H]PK 11195 made possible the autoradiographic studies on binding sites distribution. These sites were heterogeneously distributed in the grey matter and absent in white matter. Visual, auditory and other specific sensory relay stations were highly labelled. The blood pressure regulating nuclei, the vestibulo-cerebellar and the extrapyramidal motor system also presented a very high binding density. As previously described in the rat brain, choroid plexus was also strongly labelled by [3H]PK 11195 in the cat.

Animals↗